Is PKD1 p.Pro559Arg (c.1676C>G) pathogenic?

PKD1 p.Pro559Arg (c.1676C>G) is classified Uncertain significance in PKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.0977); Very rare (popmax 0.00465%, eas); Associated with polycystic kidney disease 1.

What condition is associated with PKD1 p.Pro559Arg (c.1676C>G)?

PKD1 p.Pro559Arg (c.1676C>G) is associated with polycystic kidney disease 1 (ClinVar).

How common is PKD1 p.Pro559Arg (c.1676C>G) in the general population?

PKD1 p.Pro559Arg (c.1676C>G) is very rare (popmax 0.00465%, eas) (gnomAD).

How is Autosomal dominant polycystic kidney disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PKD1 p.Pro559Arg (c.1676C>G)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

PKD1 p.Pro559Arg

c.1676C>G · VCV3579734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00465%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

polycystic kidney disease 1

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -2.1, phastCons 0.97
Regional constraint	o/e 0.78	unconstrained · MANE · 1,976 bp · p 0.00033 · regional, not allelic
Overall
CADD	7.706	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00465% East Asian · 2/43,016 alleles

Filtering AF 0.000771% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000547%

Overall 0.00115% 18/1,570,876 alleles · very rare exomes 16/1,418,686 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00465%	21,508
Remaining individualsnot grpmax-eligible	0.00164%	60,884
African / African-American	0.00135%	74,046
European (non-Finnish)	0.0012%	83,048

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PKD1
Protein: p.Pro559Arg
Coding: c.1676C>G
MANE Select: NM_001009944
Type: single nucleotide variant
Location: chr16:2116575 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

Full PKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic kidney disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant polycystic kidney disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

PKD1 p.Pro559Ala Uncertain significance ★ ⚠ same residue
PKD1 p.Pro559Leu Uncertain significance ★ ⚠ same residue
PKD1 c.10619-2A>G Pathogenic ★★ same condition
PKD1 c.10821+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.10821+2T>G Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.11017-10C>A Pathogenic/Likely pathogenic ★★ same condition
PKD1 c.11017-25A>C Likely pathogenic ★★ same condition
PKD1 c.11017-25A>G Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pkd1-p-pro559arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown